Thyroid hormone mediates a remarkable range of functions in many tissues and organ systems. These functions are important both in development and adult homeostasis. The breadth of responses raises a key question concerning the mechanisms that determine the nature, time and place of a given response to thyroid hormone. How does one hormone elicit so many different responses? Thyroid hormone receptors (TR) act as ligand-regulated transcription factors and occupy a key position in the chain of events that produce the cellular response. Two receptor genes, Thrb and Thra, encode several TR isoforms that are expressed in different developmental and tissue-specific patterns. Thus, the ability to express a given receptor isoform in a particular tissue provides a means of conferring a specific biological response. This project investigates the mechanisms that direct the unique expression patterns of different TR isoforms as a mechanism that determines specific functions of thyroid hormone. Progress: 1. The Thrb gene has an unusually large and complex structure, spanning about 400 kb on human chromosome 3 or mouse chromosome 14. Detailed mapping in mouse model strains, has identified control regions of the Thrb gene that direct tissue-specific expression of the TRb2 isoform in pituitary, cochlea and retina. A highly specialized control region lies in a non-coding, intron region of the gene. The unusual location and multi-functional nature of the control region provide a model system of biological importance in which to investigate how transcriptional mechanisms regulate chromatin structure and gene activity in different tissues. 2. To investigate the significance of these chromosomal control regions in humans, the intron and promoter regions of the mouse Thrb gene have been compared with the corresponding regions of the human THRB gene. The potential role of polymorphic changes in these sequences in the human disease of resistance to thyroid hormone is being investigated in a series of DNA samples from patients (collaboration with Dr F. Celi, NIDDK). 3. The Thrb gene also expresses a TRb1 isoform. To determine the role of this isoform, a mammalian model has been generated to investigate the functional consequences of loss of TRb1.